The incidence of esophageal adenocarcinoma (EA) is increasing dramatically in the United States and other western countries. Barrett's esophagus (BE) is a condition in which the squamous epithelium has been replaced by a metaplastic columnar epithelium. Persons with BE are at much higher risk of developing EA, but present cancer surveillance intervals are too frequent to be cost-effective, and existing medical therapies are either ineffective or invasive and expensive. The overall goals of this multidisciplinary research program are to identify molecular abnormalities, and host characteristics and exposures that predict which of the estimated 2 million person with BE in the US are most likely to progress to EA, so that prevention strategies can be developed and endoscopic surveillance intervals tailored to specific patient subsets. During our initial funding period, we validated as strong and significant predictors of progression to EA a series of biomarkers (17p LOH, increased 4N, aneuploidy, high-grade dysplasia [HGD]) that arise as manifestations of genomic instability, and identified several promising risk factors amenable to intervention. In the first aim, we will investigate earlier abnormalities that predispose to genomic instability (telomere shortening, p16 lesions, p53 mutations) as predictors of progression, using as intermediate outcomes the lesions we validated in the initial funding period (17p LOH, increased 4N, aneuploidy and HGD) in addition to EA. The second aim is to identify environmental risk and protective factors (e.g., bile reflux, overweight, NSAIDs, selenium) that modify risk of progression, and the stage(s) of progression at which they act. Cohort participants from our initial funding period (N=325) will continue to be followed for an additional 4.5 years, and new participants will be recruited to maintain cohort size. Data will be collected via in-person interviews, research endoscopies with multiple biopsies, and serum-based assays of selenium and other antioxidants. Molecular data will be collected by a robust platform developed in the initial funding period for flow cytometric cell sorting, high-throughput fluorescent genotyping and DNA sequencing as well as PNA-FISH to assess proliferation, p16 genotype, telomere length, p53 mutations, 17p LOH, increased 4N fractions and aneuploidy. Proportional hazards regression will be used to estimate the extent to which the molecular abnormalities and environmental factors predict progression to each endpoint. Successful completion of these aims will provide a scientific basis for i) prevention trials using candidate interventions and validated intermediate endpoints, and ii) a more rational surveillance strategy for BE.